UCtelevision — April 08, 2010 — Dr. Donald Abrams of UCSF sifts through some of the complex data on the relationship between nutrition and cancer and endeavors to help separate fact from fiction in this quickly moving field. Series: Integrative Medicine Today [5/2010] [Health and Medicine]
This article was forwarded to me by one my clients who happens to be a top-tier cancer researcher. It looks specifically at calorie restriction (CR) as a way to inhibit carcinogenesis. However, nearly all of the benefits of CR can be achieved without limiting calories - especially insulin control, inflammation reduction, limiting estrogen and IGF-1, decreases in leptin, and increases in adiponectin (this list includes nearly all of the factors mentioned as benefits of calorie reduction). These all can be achieved with a low-carb, healthy fats diet high in lean protein that serves to control insulin and reduce inflammation. Add in some alpha lipoic acid and some resveratrol and you will probably be ahead of the game.
Stephen D.Hursting, Sarah M.Smith, Laura M.Lashinger, Alison E.Harvey, & Susan N.Perkins. (2009). Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis; 31:1, pp.83–89. doi:10.1093/carcin/bgp280Read the whole article online.
Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers. This review synthesizes the evidence on key biological mechanisms underlying many of the beneficial effects of CR, with particular emphasis on the impact of CR on growth factor signaling pathways and inflammatory processes and on the emerging development of pharmacological mimetics of CR. These approaches will facilitate the translation of CR research into effective strategies for cancer prevention in humans.
Introduction
Over the past 30 years, calorie restriction (CR), an experimental mode in which test animals receive a lower-calorie diet than ad libitum-fed controls, has emerged as the most potent, broadly acting dietary intervention for preventing carcinogenesis in rodent models of cancer (1). Carcinogenesis has published many of these studies, most involving rodent models of chemically induced or oncogene-driven cancer, in >40 papers over the course of its 30 year history. Recent reports of extended life span and delayed cancer development in response to CR in rhesus monkeys (2) and observations that CR during the premenopausal years decreases postmenopausal breast cancer risk in women (3) suggest the anticancer effects of CR reported in rodent models extend to primates, including humans. The rhesus monkey study (2) involved 46 male and 30 female rhesus macaques (aged 7–14 years at the start of the study), randomized to receive a control diet regimen or a 30% CR regimen and followed for 20 years. Each CR animal’s baseline energy intake was reduced by 10% each month over a 3 month period and then maintained for the duration of the study to achieve the desired 30% CR. The CR regimen reduced the incidence of cancer, cardiovascular disease and brain atrophy, and 80% of the CR animals were still alive compared with 50% of the controls at the time of the report. These are important and encouraging findings that suggest the mechanisms characterized in animal model studies, and their translation into intervention targets and strategies, will have relevance to the prevention and treatment of cancer (particularly those related to obesity) in humans.
This review summarizes key findings on the biological mechanisms underlying many of the anticancer effects of CR. It also describes some of the opportunities now available for investigation that will facilitate the translation of CR research into effective strategies to prevent human cancer. The review is based on a MEDLINE database search (from 1 September 1979 through 1 September 2009) for the key words (cancer or carcinogenesis) and (‘food restriction’ or ‘dietary energy restriction’ or ‘energy restriction’ or ‘caloric restriction’ or ‘calorie restriction’ or ‘diet restriction’ or ‘dietary restriction’). Reviews, editorials and primary journal articles identified by this search, along with chapters from textbooks on dietary restriction and cancer available at the University of Texas library were reviewed in order to summarize our current knowledge of the effects and possible underlying mechanisms of CR on the carcinogenesis process.
Translational potential of CR in humans
As we have previously reviewed, observational studies further support the notion that CR has beneficial effects on longevity and cancer risk in humans (4). For example, moderately reduced caloric intake decreased morbidity and mortality among Spanish nursing home residents (5). In addition, inhabitants of Okinawa, Japan, who until recently consumed significantly fewer calories than residents of the main Japanese islands, have lower death rates from a broad spectrum of cancers and other chronic diseases than inhabitants of the Japanese mainland (6). Furthermore, patients with early-onset anorexia nervosa, and hence periods of energy restriction, have reduced risk of breast cancer (7). Another population who may experience a similarly reduced risk of such cancers are women affected by the female athlete triad. The defining characteristic of this syndrome is insufficient calorie intake (which may reflect a psychopathological eating disorder like anorexia nervosa and/or bulimia or simple lack of sufficient nutritional knowledge on the part of the female athlete) in the face of high levels of physical activity; low energy availability leads to the other legs of the triad, menstrual dysfunction and decreased bone mineral density (8). While the true prevalence of the female athlete triad among both female athletes and the general active population is difficult to ascertain, the significant expansion in opportunities for American women to participate in sports after passage of Title IX legislation in 1972 implies that a larger proportion of this cohort may be affected than in previous generations. There are no published reports examining the effect of low energy intake in this population on cancer risk; however, affected women, while they are at increased risk of long-term health problems like osteoporosis, may also be expected to experience decreased risk of breast cancer, similar to the examples cited above.
Data from countries that experienced varying degrees of energy restriction during World War II are also informative. For example, a cohort of Norwegians showed reduced breast cancer risk in the face of acute (<1>80% reduction in usual energy intake) energy restriction, such as European Jewish survivors exposed to the Holocaust (11) or Russian survivors of the Siege of Leningrad (12), actually show increased risk of some cancers. The confounding effects of severe physical and psychosocial stress, malnutrition, infection and other factors associated with war conditions make these studies challenging to interpret. However, based on data from animal and human studies, it does seem clear that while CR typically decreases cancer risk, the anticancer effects associated with reduced energy intake can be neutralized or overwhelmed in the presence of extreme stressors, such as occurred during World War II.
These multifaceted stressful conditions were very different than the experimental conditions characteristic of the majority of the published CR studies in animal models that consistently show anticancer effects. CR is often referred to as ‘undernutrition without malnutrition’, and CR experiments typically involve 10–40% reduction in calories relative to controls coupled with adequate nutrition and a controlled physical environment (4). CR regimens administered throughout life are generally more protective than adult-onset CR (4). However, both early-onset and adult-onset CR prevent adult-onset obesity, significantly extend life span, and suppress tumorigenesis, prompting many investigators to suggest that obesity prevention may be a key underlying factor in the anticancer effects of CR (1,4). Rodents allowed to consume food freely become overweight, even obese, depending on the strain and diet. As Pariza et al. noted, the long-time under appreciation of CR in cancer research was probably due to ‘a problem in terminology’ (13) in that ‘more interest might have been aroused . . . if the freely fed mice had been described as obese instead of the mice on the restricted diet being described as small!’ (14).
There are several National Institute of Aging-funded clinical trials underway to test the effects of CR in humans under controlled conditions on biomarkers of age-related diseases processes, including cancer, to determine the similarities and differences of CR responses in humans relative to the well-characterized effects of CR in rodents. Although each of these long-term trials is in the early stages, a preliminary report of biomarker responses in one of these studies (termed the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Study conducted at the Pennington Biomedical Research Center) indicates that many of the same metabolic and endocrine changes observed in rodents and monkeys may be also occurring in humans in response to CR (15,16).
Consistent with these preliminary findings in the National Institute of Aging trials of the effects of CR on biomarkers of age-related disease processes are findings from Biosphere 2 (17) and a Netherlands Toxicology and Nutrition Institute study (18). Biosphere 2, which took place in a closed ecosystem in Arizona from 1991–1993, involved four men and four women who experienced, on average, a 30% restriction in calorie intake relative to their usual energy intake prior to the 2 year Biosphere project. Although this sample was too small and uncontrolled to allow clear conclusions, many of the physiological parameters associated with the anticancer effects of CR in rodents and non-human primates were observed in these subjects (17). A TNO Toxicology and Nutrition Institute study in the Netherlands was more controlled, with 8 ad libitum control subjects and 16 subjects on a 20% CR regimen relative to their usual intake for 10 weeks. As in Biosphere 2, the TNO study subjects on the CR regimen, relative to the controls, displayed positive health effects, including decreased fat mass, lowered blood pressure and improved blood lipid and other chemistry values (18).
Obesity is an important risk factor for several chronic diseases, including many cancers. Translation of the CR phenomenon to human chronic disease prevention is especially critical considering that obesity is increasing alarmingly throughout the world (19). Given these trends, the development of intervention strategies that either prevent obesity or disrupt the mechanistic link underlying obesity and carcinogenesis will become increasingly critical in the coming years. Important insights into this problem can be found in the extensive literature on CR and carcinogenesis, which we have attempted to summarize over the past several years. Unfortunately, the mechanisms responsible for the observed effects of CR on cancer and other chronic diseases are not yet clearly elucidated.
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